Human X-linked immunodeficiency diseases (XLID) are associated with defective lymphoid development or abnormal lymphoid function. The overall goal of this project is to isolate and characterize: 1) the genes that are defective in some of these XLID, including X-linked agammaglobulinemia, X- linked severe combined immunodeficiency, and the Wiskott-Aldrich syndrome, and 2) other human X-linked lymphocyte-regulated (XLR) genes that control lymphoid development. XLR genes will be isolated from a genomic X- chromosome library by differential and subtractive hybridization approaches with cDNA probes generated from RNA of various sources that represent discrete stages of lymphoid development. Isolated XLR clones will be studied for gene expression at various stages of human and murine lymphoid development. cDNA XLR clones will be isolated and sequenced. The XLR clones will be mapped by physical and genetic approaches to determine whether XLR gene clones represent XLID genes. Physical mapping will be performed by regional deletion analysis with somatic-cell hybrids and by in-situ hybridization. The XLR gene clones will be used for linkage analysis in families with members with XLID. Gene structure and expression in XLID patients will be studied. The structure and function of the XLR and XLID genes will be characterized. The results of this proposal should contribute to understanding lymphocyte commitment, development, and function, and be applicable to the diagnosis and treatment of XLID and lymphoid malignancy.